1. Field of Invention
The present invention relates to the use of stabilized chlorine dioxide in topical oral compositions to prevent oral fungal infections.
2. Description of Related art
Thrush, clinically termed oral candidiasis, is the most common opportunistic fungal infection in humans. Thrush is caused by the imbalance of microorganisms in the oral cavity allowing Candida species (fungus or yeast) to grow out of control causing infection with development of white lesions and potentially spreading to other parts of the body, including the esophagus, lungs, liver, and skin. Four types of oral thrush are recognized: angular cheilitis, denture stomatitis, erythematous candidiasis, and pseudomembranous candidiasis. Thrush may involve several species of Candida resident in the oral ecology, each with its own characteristics and susceptibility to treatments.
Candida species are found in the oral cavity as normal commensal microorganisms and may overgrow when the host response is weakened, such as in immunocompromised individuals. Immunocompromised conditions include HIV/AIDS, nutritional deficiencies, metabolic disorders such as diabetes, malignancies, xerostomia, medication side effects, aging, pregnancy, Sjogrens syndrome, dentures, and smokers.
The amount of Candida colonization in the oral cavity of denture wearers was higher (Abu-Elteen and Abu-Alteen, 1998). Studies that observed oral cavities of immunocompromised patients indicate that patients who wore dentures were associated with increased numbers of yeasts, more specifically Candida species (Willis et al., 1999; Gonclaves et al., 2006).
The oral microbiological environment can be significantly affected by tobacco smoking, specifically having an effect on oral bacteria and fungi, particularly Candida. The impact of smoking on thrush varies in combination to pre-existing conditions (dentures, HIV, and diabetes) (Soysa and Ellepola, 2005). Increasingly, studies show smokers have greater numbers of oral Candida carriage than non-smokers (Abu-Elteen and Abu-Alteen, 1998; Willis et al., 1999). Several studies suggest that smoking has a significant affect on the incidence of thrush in immunocompromised patients. Smoking is an important risk indicator for thrush, especially in HIV infected patients (Chattopadhyay et al., 2005). Conley et al. (1996), Campisis et al. (2002), and Slavinsky et al. (2002) found significant associations between thrush and smoking in HIV infected individuals. Willis et al. (1999) reported that seventy seven percent (77%) of diabetic patients carried Candida species in the mouth. Among these patients, there was a significant increase in the tobacco smokers. Smoking alone or in combination with other factors may be contributory to the development of thrush.
Thrush is the most common and earliest oral manifestation of HIV/AIDS caused mostly by Candida species. HIV/AIDS patients commonly have dry mouth, pain and may develop oral lesions from thrush, which can interfere with oral intake of food and lead to severe malnutrition. HIV related oral manifestations occur in an estimated 30-80% of HIV patients and are often under diagnosed and misdiagnosed. Thrush will develop in up to 90% of all advanced untreated HIV infections, with 60% experiencing at least one episode per year with recurrences. (Samaranayake et al., 1989; McCarthy et al., 1991). Thrush is often the first indicator of progression from HIV to AIDS; this was confirmed in a study by Sharma et al. (2006) who showed that there was a 2.5 time increased risk of progression from HIV to AIDS in patients with thrush. The progression indicates the immunological decline and is manifest by decreased CD4+ T-lymphocyte cell counts, which contribute to the risk of developing both thrush and oral hairy leukoplakia. Chattopadhyay et al. (2005 and 2007) reported a correlation that showed low CD4+ counts and smoking are independent risk factors for thrush and oral hairy leukoplakia.
Cancer treatments, cytoxic chemotherapy and radiotherapy, have short and long term side effects including thrush. The incidence of thrush in cancer patients ranges widely depending on the stage of the cancer, doses of treatments, method of diagnosis and other predisposing factors. Davies et al. (2006) found that 66% of cancer patients carried oral Candida and other yeast species and 30% had thrush. Another study reported 25% of patients receiving radiation for head and neck cancer had high prevalence of Candida colonization in the oral cavity (Redding et al., 2004). There is evidence that thrush can also spread to the esophagus and develop esophageal candidiasis (Samonis et al., 1998). This finding underscores the importance of preventing and reducing the risk of thrush in all immunocompromised patients.
Diabetes mellitus patients have increased susceptibility to certain infections, which can lead to poor metabolic control. Studies have shown that oral candidal infections are more common in diabetic patients than in non-diabetics. Takasawa, et al. (2006) reported a case study of the association of diabetes with thrush. The case involved a 75-year old healthy patient who developed diabetes and candidiasis (oral and esophageal) within a short interval with limited risk factors. The patient was diagnosed with type 2 diabetes accompanied by severe thrush and esophageal candidiasis. The case indicates a relationship between diabetes and oral infection, wherein diabetes may cause oral infections and conversely oral infection may stimulate the development of diabetes (Taylor, 2008).
Candida species have been isolated from oral cavities of diabetic patients. Willis et al., 1999 found 77% of diabetic patients carried oral Candida species. This study also established that a number of contributory factors affect candidal colonization; these include smoking, dentures, type and duration of diabetes and the degree of glycaemic control. Willis et al. also isolated several different species of Candida in combination to the predominate species, Candida albicans. Goncalves et al. (2006) investigated the oral yeast colonization and antifungal susceptibility in diabetic patients, isolating several non-albican species, including C. tropicalis, C. glabrata, C. krusei, C. rugosa, C. guillermondii, and C. parapsilosis. This study tested the resistance of these species to the antifungal treatment fluconazole, and found high levels of resistance by the non-albican species.
Treatment and therapy of thrush varies with each medical condition. Prevalent recommended therapies currently include nystatin, azole antifungal agents and amphotericin B preparations. Initial episodes of oral thrush in healthy children and adults can be treated effectively with topical therapies, including clotrimazole troches, nystatin suspensions or pastilles (Rex et al., 2000); however, individuals with immunocompromised systems will often have recurrent episodes of infections making it difficult to treat with these therapies. A resistance to the therapies may also develop with any regimen. Most patients will initially respond to topical therapies; however, immunocompromised patients will often experience symptomatic relapses sooner.
Oral azoles, nystatin, amphotericin B, and chlorhexidine are several therapies administered orally for the treatment of oral thrush. The azoles include fluconazole, itraconazole, and ketoconazole, which can be capsules/tablets or liquid suspensions taken by mouth and absorbed by the gastrointestinal tract. Oral fluconazole is better tolerated than itraconazole and ketoconazole. Capsule azoles are found to be less effective than the oral suspensions due to variable absorption. Nystatin and amphotericin B are less effective at preventing fungal infections than prophylactic therapies with fluconazole. Most recurring infections are due to prior use of the therapies where the fungi developed resistance to the treatments; individuals with recurring infections must change from one oral treatment to other treatments over time. For instance, thrush infections resistant to fluconazole will respond to oral itraconazole about two-thirds of the time. When the patient is not responding to itraconazole, amphotericin B oral suspension may be effective. A high dose of medication for a short period is recommended to reduce the development of candidal resistance.
Chlorhexidine gluconate (CHX) has antifungal properties, and it is widely used by dental professionals as an antimicrobial oral rinse. While it may be effectively used as a preventive to the development of thrush, it has not been proven effective as a treatment. Objectional taste and teeth staining lead to problematic use of CHX continuously. Worthington et al. (2008) reviewed literature pertaining to the effectiveness of interventions and medications for treating thrush in cancer patients, concluding that drugs absorbed or partially absorbed from the GI tract are more effective than those not absorbed (including nystatin and amphotericin B).
Candida albicans is usually the predominant species in thrush, however other species of Candida have been emerging as significant pathogens in patients. Non-albicans species of Candida have been isolated in combination with C. albicans in cancer and HIV patients. They have been observed to cause more severe immunosuppression, and consequently are more difficult to treat. Cartledge et al. (1999) reported that from 100 non-albicans isolates obtained from HIV patients with thrush, 88 were resistant to fluconazole. There is a need for a treatment with high susceptibility to all types Candida species.
Non-albicans species commonly found in saliva of patients with oral lesions (with or without oral thrush) include C. tropicalis, C. glabrata, C. parapsilosis, C. Krusei, and C. dubliniensis (Oliveria et al., 2007; Coleman et al., 1997). A study by Davies et al. showed 25% of samples taken involved non-albicans species (including C. glabrata, C. dubliniensis, and C. tropicalis) were the predominant organisms and a contributing factor in 19% of samples taken from cancer patients with thrush (2006).
Candida glabrata, formerly known as Torulopsis glabrata, is a significant human pathogen and is the second leading cause of oral thrush (Li et al., 2007). Its association with thrush is unclear as some research suggests that it is only a commensal organism and does not contribute directly to infections. However, it is also observed that its presence with C. albicans in HIV-positive patients present more severe and difficult to treat forms of thrush, requiring higher doses of fluconazole medication. Other treatments for C. glabrata infections include itraconazole and amphotericin B solutions; however much like other treatments for fungal infections, a percentage of C. glabrata treated with these medications become resistant to them. C. glabrata is dose-dependent to fluconazole, and may require higher doses than does Candida albicans in order to be effective. The C. glabrata is the second most frequent species in elderly patients with and without dentures. Lockhart et al. found that patients with dentures had an increase in C. glabrata frequency from 36% to 58% in elderly ages 70-79 yrs and 80 years and older, respectively (1999). Candida glabrata is an increasingly common species found in all cases of thrush infections and is very difficult to treat due to its resistance to commonly used drugs.
Candida dubliniensis has been found mostly in oral cavities of HIV-positive and AIDS patients, especially those that received fluconazole therapy. C. dubliniensis has phenotypic characteristics similar to C. albicans and displays the same antifungal susceptibilities. Research has found that fluconazole can be ineffective for managing diverse infections that include C. albicans and C. dubliniensis species due to their combined development of resistance to the drug (Moran et al., 1997). HIV-positive patients with large doses of medications are more vulnerable to developing resistance. C. dubliniensis has been effectively treated with several common azoles therapies including ketoconazole, itraconazole, and amphotericin B. C. dubliniensis is also susceptible to triazoles, including voriconazole, posaconazole and ravuconazole.
Candida krusei colonization in the oral cavity is increasingly common. Thrush with C. krusei also includes the presence of C. albicans. Itraconazole solutions were proven effective in treating Candida krusei in thrush patients, but C. krusei infections were resistant to both fluconazole and ketoconazole (Cartledge et al., 1999).
Thrush caused by the colonization of Candida tropicalis is rare and is susceptible to any antifungal treatment. However, its presence in thrush of cancer patients receiving chemotherapy can be very pathogenic and may lead to hemotologic infections.
New orally administered, ingested antifungal drugs, including terbafine, azoles, and echnocandins, are currently being tested as treatments of thrush. Studies show these new drugs may be more effective in treating thrush involving non-albicans infections. For instance, Bagg et al. (2005) shows in vitro tests of voriconazole to be effective on fungal oral infections which are resistant to other antifungals including fluconazole and itraconazole. However, this study also showed C. glabrata not to be fully susceptible to voriconazole. Voriconazole must be administered with care due to its significant drug interactions and its contraindication with several other drugs.
There is a limited capacity of current pharmaceutical drugs to prevent and treat Candida infections. Candida species are recognized to become resistant to most fungicidal treatments over time, and different species are more or less resistant to treatment and various medications. In several cases, the resistance to antifungals can be reduced with use at higher doses but such dosing only can be used for a short time (Rose, 2004). Certain individuals suffering from oral thrush (cancer, HIV, and diabetes) require extended treatments that correspond to their medical conditions. Similarly, pregnant women and the elderly may require oral thrush treatments extending over several months and therefore may not be able to use the higher dosages over extended time without untoward consequences. Immunocompromised patients often are diagnosed with underlying conditions that require several medications, complicating treatment with the prospect of negative drug interactions. Given the limitations of antifungals' effectiveness against candidal infections, the higher doses may be useful and appropriate largely for mild cases because most severe cases require longer periods of treatment.
The treatment of thrush becomes particularly difficult when several different Candida species are present and when other existing systemic conditions complicate treatment. Prevention of thrush among populations most at risk is preferable than treatment because it permits immunocompromised patients to maintain their health and diet and may lead to less severe and/or less frequent cases. Therefore, there is a need for a composition for both the prevention and the treatment of thrush, which is safe and effective in inhibiting, reducing and eliminating all oral Candida species involved in infections.